Non-insulin dependent diabetes (NIDDM) has a strong genetic predisposition, but the mode of inheritance, the number of loci and the specific mutations which cause common NIDDM are unknown. Biochemical and physiological studies of NIDDM have failed to identify a predisposition. In studies of 16 pedigrees with multiple affected members (familial NIDDM) ascertained in our laboratory, we demonstrated that pedigree members were hyperinsulinemic and we excluded multiple candidate genes as major loci predisposing to NIDDM. We propose to expand these studies by using the human genome map and linkage analysis to test the hypothesis that a major genetic locus predisposes to familial NIDDM. Unaffected members of previously ascertained pedigrees will be examined to update affection status and to obtain more accurate measures of fasting insulin. An additional 10 pedigrees will be ascertained, the members examined, and cell lines established. The role of fasting hyperinsulinemia as a segregating prediabetic marker will be evaluated in this expanded cohort, and age of onset, obesity, and fasting insulin will be examined as markers for clinical subgroups. We will systematically type highly informative markers for each chromosome, beginning with candidate regions which have not been examined previously. These data will be analyzed for linkage under dominant and recessive models and by affected pedigree member methods to ensure detection of a major genetic locus. To confirm or reject linkage, we will type additional markers in any regions for which 10;1 odds for linkage are present on initial analysis. At minimum, our proposed studies will determine whether a single gene exists which accounts for >70% of familial NIDDM in this population. If that gene exists, our studies will lead to the identification of the precise mutation. We also present a comprehensive plan to increase our power to detect loci which are linked in fewer than 50% of pedigrees. This strategy includes stratification of pedigrees based on predetermined clinical parameters. If we do not initially detect linkage with this comprehensive approach, our proposed studies will direct future candidate gene studies and contribute to collaborative efforts to identify NIDDM predisposition under heterogeneous models. Our studies will help clarify the role of genetic predisposition in NIDDM pathogenesis and will provide essential data in the prevention and cure of diabetes.